Intranasal drug delivery

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Intranasal drug delivery occurs when particles are inhaled into the nasal cavity and transported directly into the nervous system. Though pharmaceuticals can be injected into the nose, some concerns include injuries, infection, and safe disposal. Studies demonstrate improved patient compliance with inhalation. Treating brain diseases has been a challenge due to the blood brain barrier. Previous studies evaluated the efficacy of delivery therapeutics through intranasal route for brain diseases and mental health conditions. Intranasal administration is a potential route associated with high drug transfer from nose to brain and drug bioavailability. [1]

Contents

History of drug delivery

Drug delivery is a process of administering therapeutics to treat human diseases. The first drug delivery system is often dated to the 1950s, when Smith Kline & French Laboratories introduced the Spansule technology. [2] Between 1950s and 1980s, there were four drug release systems developed for oral and transdermal applications: dissolution, diffusion, osmosis, and ion-exchange controlled release. [3] Later in the 1980s, the Lupron Depot technology further advanced the field by offering zero-order and long-term release systems. The intranasal route gained interest towards the end of the 20th century with treating cardiovascular and respiratory diseases. During the late 1980s, William Frey II studied the intranasal route for treating brain diseases. Ever since, it has become a potential route for nose-to-brain delivery.[ medical citation needed ] [4]

Anatomy

Intranasal delivery pathway

Pathway of inhaled particles from nose to brain. Nose-to-Brain Drug Pathway.png
Pathway of inhaled particles from nose to brain.
The olfactory region contains the olfactory nerve and bulb. Olfactory nerve is a network of fibers which connect to the olfactory bulb. When particles reach the bulb, they have access to different regions of the brain. Olfactory region.png
The olfactory region contains the olfactory nerve and bulb. Olfactory nerve is a network of fibers which connect to the olfactory bulb. When particles reach the bulb, they have access to different regions of the brain.

The nasal cavity is highly vascularized, allowing efficient transfer of molecules directly to the nervous system. Compared to other administration routes, nasal drug delivery increases bioavailability and reduces systemic exposure risks. The nasal cavity’s slightly acidic environment and enzymes can affect drug degradation, making delivery systems with neutral to acidic pH ideal. The respiratory region, with its large surface area and high vascularization, is the primary site for drug absorption into systemic circulation. Targeting the olfactory region enhances nose-to-brain drug delivery, as particles can travel via the olfactory nerve to the brain. This route offers potential for treating brain diseases and mental health conditions. [5]

Blood brain barrier

Depiction of all the different barriers in the brain. Focusing on (i), the blood brain barrier (BBB) is a highly selective membrane. It only allows passage of specific particles based on physiochemical properties. Protective barriers of the brain.jpg
Depiction of all the different barriers in the brain. Focusing on (i), the blood brain barrier (BBB) is a highly selective membrane. It only allows passage of specific particles based on physiochemical properties.

The blood-brain barrier (BBB) is a semipermeable membrane that separates the blood from the brain’s interstitial fluid. It is formed by tight junctions between endothelial cells, astrocytes, and pericytes in the brain’s capillaries, and has high electrical resistance. The BBB is crucial for protecting the brain from pathogens and toxic substances, maintaining homeostasis, and preventing alterations to neuronal functions. However, some diseases can damage the BBB, causing leakage. Research suggests that increasing intake of vitamins and antioxidants, as well as reducing stress, can help restore the BBB. Due to its selective nature, the BBB restricts the passive diffusion of solutes, large and hydrophilic molecules, and immune factors, making it challenging to deliver pharmaceuticals directly to the brain. [6]

Recent studies on nose-to-brain drug delivery

Alzheimer's

Neurodegenerative diseases occur from loss of neuronal structure and function. This progressive degeneration of neurons is irreversible. Alzheimer's is a neurodegenerative disease that begins with short-term memory loss progressing to loss of control over heartbeat and breathing. It has been over 100 years since Alois Alzheimer first presented the world disease to the world in 1906. There is evidence for the efficacy of intranasal delivery to treat Alzheimer's. Intranasal delivery of insulin showed greater memory improvement in patients with Alzheimer's than in healthy individuals. [7] Increased microglial activation inflammation are characteristics of Alzheimer's. Animal studies show intranasal administration of pro-resolving lipid mediators decreased both factors, slowing pathogenesis of this disease. [8] Delivering a novel peptide via intranasal route reduced amyloid beta plaques, a defining trait of Alzheimer's and enhanced cognitive functions. [9] Intranasal delivery of anti-Alzheimer's drug dispersed through hydrogel in rabbits demonstrated higher bioavailability compared to oral tablets. [10] MiR132 is an RNA molecule that regulates neuronal morphology and maintains survival. This molecule is downregulated with Alzheimer's. A study administered PEG-PLA nanoparticles loaded with this miRNA to mice through the nasal route. This novel therapy showed increased expression of miR132 and improved memory function. [11] To strengthen the effectiveness of intranasal delivery, there are studies to develop permeation enhancers to better improve drug transport across the blood brain barrier. [12]

Glioblastoma

Abnormal cell growth and formation of mass in the brain tissue or nearby regions may cause brain cancer. Constant headaches, seizures, and blurred vision are common symptoms. Glioblastoma (GBM) is the most fast-growing and deadliest brain tumor. Though the main cause of glioblastoma remains unknown, it originates when astrocytes mutate and multiply uncontrollably forming tumors in the frontal and temporal lobes of the brain. The challenge with current therapeutics is to initiate tumor cell apoptosis with no toxic effects to healthy brain tissue. Nanoparticles loaded with chemotherapeutics delivered through the intranasal route show promising results in treating glioblastoma. PLGA-based nanoparticles loaded with paclitaxel or doxorubicin conjugated with a RGD sequence targeted the glioblastoma microenvironment and reduced tumor volume through cell death. [13] [14] MicroRNA-21 (miR-21) inhibits pro-apoptotic genes increasing progression of glioblastoma. Self-assembling nanoparticles produced with anti-tumor peptides were administered intranasally and reduced miR-21 levels increasing tumor cell apoptosis. [15]

Epilepsy

Infection, head injury, or strokes can cause sudden bursts of neuronal activity leading to abnormal behaviors, muscle movement, and mood changes. This condition is known as seizure. Epilepsy is characterized by recurring seizures. Some possible causes of epilepsy include imbalance or disruption of neurotransmitters, strokes, or brain injury. Intranasal delivery of carbamazepine nanoparticles increase antiepileptic drug bioavailability. [16] Administering a self-assembling hydrogel with neuroactive drugs to treat Parkinson's disease appears to be biocompatible, low in toxicity, and have a good recovery capacity. Nasal delivery of this gel demonstrated increased drug concentration in the brain. [17] Oxytocin is a hormone which is observed to alleviate anxiety symptoms in people with autism. Intranasal administration indicated efficient transfer of pharmacologically active oxytocin from nasal cavity to brain. [18]

Parkinson's

Similar to Alzheimer's, Parkinson's is the most common neurodegenerative disease associated with balance and coordination issues, muscle stiffness, and tremors. During the early 1800s, James Parkinson medically defined this disease. A study observed improvement in locomotor abilities in rats with Parkinson's after intranasal delivery of conjugated mitochondrial systems. [19] Another study demonstrated delivery of neuroactive drugs in a hydrogel increased residence times in the nasal cavity and concentration in the brain. [20] Administering therapeutics combined with nanocarriers is shown to directly transfer drugs to the target cells and enhance accumulation. The observed effects include improved neuronal signaling and locomotion. [21] Furthermore, intranasal delivery of biodegradable nanoparticles surface-modified with lactoferrin increase accumulation in the brain and cellular uptake. [22]

Depression

Characterized by loss of neuroplasticity, depression is a common mood disorder causing persistent negative emotions and changes in lifestyle. Intranasal delivery of relaxin-3 mimetics demonstrated significant anti-depressant activity in behavior paradigms of rat models. [23] Delivering a thermoresponsive hydrogel loaded with berberine intranasally exhibited high bioavailability in hippocampus and anti-depressant activity. [24]

Anxiety

Anxiety can impair hippocampus function which increases risk of depression and dementia. Anxiolytic effects were observed in animal models post-intranasal delivery of a loaded polymeric nanoparticles. [25] Another study indicated intranasal delivery of neuropeptide Y lowered anxiety in rats. [26]

Anorexia nervosa

Anorexia nervosa (AN) is a common eating disorder characterized by low intake of food from fear of weight gain. Several complications are associated with this chronic disorder such as fatigue, insomnia, and low blood pressure. Intranasal administration of oxytocin in patients with AN significantly lowered food anticipation and eating concern. [27]

Substance use disorder

Uncontrolled and continuous use of a substance, drugs or alcohol, is known as substance use disorder. Substances can interfere with neuronal signaling and potentially disrupt the brain circuit. Addiction to these substances impairs thinking, behavior, and other biological functions. Intranasal delivery of insulin is associated with improvement in brain metabolic activities and alleviate impulsivity. [28] Opioid addiction is prevalent and associated with many substance abuse deaths. A study observed high biodistribution in the brain and reduction in opioid overdose in rats administered with naloxone-loaded lipid nanoparticles. [29]

Post-traumatic stress disorder

Witnessing a devastating or terrifying situation can lead to post-traumatic stress disorder (PTSD). This mental health condition triggers anxiety, depression, and extreme fear with memories. Intranasal administration of temperature-sensitive hydrogels loaded with PTSD medications showed enhanced brain targeting effects and tissue distribution. [30] Similarly, another study observed anti-PTSD effects with intranasal administration of loaded hydrogels. [31]

Schizophrenia

Schizophrenia is a chronic mental health condition caused by changes in brain chemistry and structure. Genetics and environment are hypothesized to play a key role in development of this disorder. Research suggests impaired gene expression or chemical imbalance may impact this condition. Anxiety can increase risk of schizophrenia and symptoms include hallucinations, disorganized speech, and abnormal behavior. Davunetide (NAP) is a segment of activity-dependent neuroprotective protein (ADNP). ADNP is reported be downregulated with schizophrenia. A study observed decreased hyperactivity in mice when treated with NAP via the intranasal route. [32]

Migraine

Migraine occurs with episodes of intense headache causing nausea and throbbing pain. Stress and hormonal changes can be a trigger migraine. A nasal spray containing sumatriptan demonstrated a significant reduction of migraine pain. Further clinical studies of intranasal administration of sumatriptan (ST) can help evaluate efficacy and safety of such delivery systems. [33] Since its approval by the FDA in 2021, dihydroergotamine mesylate has been administered through nasal sprays to treat migraines. [34] [35]

Nanosystems for Intranasal Drug Delivery

Depiction of a lipid-based nanoparticle, liposome. The phospholipid bilayer exhibits amphipathic properties which allows encapsulation of hydrophilic and hydrophobic molecules. Liposome.jpg
Depiction of a lipid-based nanoparticle, liposome. The phospholipid bilayer exhibits amphipathic properties which allows encapsulation of hydrophilic and hydrophobic molecules.

Nanoparticles are drug delivery systems ranging from 1–1000 nm in diameter. Lipid-based and polymer-based nanocarriers are commonly used for nose-to-brain delivery as they exert high stability, solubility, and adherence. [36] Exosomes and dendrimers are other potential nanocarriers. Nanosystems can be synthesized either using physical or chemical methods. A few physical methods include evaporation-condensation reaction and laser ablation. Irradiation, microemulsion, and chemical reduction are common chemical techniques to develop nanoparticles. Sonication, electroporation, and incubation are common methods to load drugs into nanocarriers.

Coating these nanosystems with mucoadhesive agents, stimulus-sensitive materials, or antibodies can enhance biocompatibility, clearance rates, specificity, and bioavailability. Penetration and absorption enhancers can significantly increase the overall efficacy of the system. Imaging studies along with measurement of drug transfer efficiency and bioavailability can further support the role of these drug delivery systems.

Lipid-based nanoparticles

Lipid-based nanoparticles (LNP) can deliver molecules with low toxicity and controlled release. Liposomes, solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), and nanoemulsions are examples.

Liposomes are made up of phospholipids forming spherical vesicles. This property enables liposomes to exhibit high biocompatibility and biodegradability. Studies report potential application of liposomes to treat brain diseases due to increased retention and absorption in nasal cavity, and high brain biodistribution. [37] A previous study developed a cationic liposome loaded with mRNA and green fluorescent protein (GFP). Intranasal delivery of this formulation in murine models demonstrated high brain biodistribution and expression of mRNA-GFP. [38]

Solid lipid nanoparticles (SLNs) are made up of solid lipids forming a matrix and stabilized by surfactants. They exhibit high physical stability and remain in solid state at different temperatures. Based on a study, intranasal delivery of SLNs loaded with rivastigmine tartrate (RT) exhibited no toxicity, stability, and improved bioavailability. [39] Sometimes burst release may occur due to rigidity and less flexibility in shape.

Nanostructured lipid carriers (NLC) are synthesized by a mixture of solid and aqueous lipids. NLC's are developed from SLNs, thus referred to as second generation LNPs. Intranasal administration of NLC loaded with curcumin (CRM) increased biodistribution and concentration in brain after emerging as a potential system for brain cancer. [40]

Small colloidal systems made of micelles containing oil, aqueous phases, and emulsifiers are called nanoemulsions. Intranasal delivery of gel nanoemulsion loaded with temozolomide is observed to exhibit sustained release and better permeation from nose to brain to treat glioblastoma. [41]

Polymer-based nanoparticles

Depiction of a type of polymer-based nanoparticle. Nanospheres contain a uniformly dispersed drug encapsulated in a polymeric core and matrix. Nanosphere.png
Depiction of a type of polymer-based nanoparticle. Nanospheres contain a uniformly dispersed drug encapsulated in a polymeric core and matrix.
Depiction of a polymer-based nanoparticle. Nanocapsules consist of drugs encapsulated in a polymeric membrane. Nanocapsule.png
Depiction of a polymer-based nanoparticle. Nanocapsules consist of drugs encapsulated in a polymeric membrane.

Polymer-based nanoparticles can be made from either natural or synthetic sources. Nanospheres and nanocapsules are polymeric nanoparticle systems. Natural polymers can be found in the environment or human body. On the other hand, synthetic polymers do not occur naturally and are artificially developed polymers with chemical modifications. Natural polymer-based nanoparticles can be made up of chitosan, hyaluronic acid, alginate, and gelatin. Natural polymers exhibit excellent biocompatibility and biodegradability, and low toxicity. Synthetic polymer-based nanoparticles can consist of poly (glycolic acid) (PGA), poly (lactic acid) (PLA), and poly(L-lactide-co-glycolide) (PLGA).

A study evaluated chitosan nanoparticles loaded with an anti-epileptic drug, phenytoin (PHT), to treat epilepsy. Observations suggested high stability, sustained release, and bioavailability when these particles where administered via the intranasal route. [42] Similarly, administering PLGA nanoparticles loaded lamotrigine (LTG), polymer-based nanoparticle, showed better permeation through BBB and higher bioavailability. [43]

Exosomes

Depiction of exosome formation. Following invagination of the plasma membrane, multivesicular bodies (MVBs) form and fuse with membrane to release exosomes. Exosome formation.png
Depiction of exosome formation. Following invagination of the plasma membrane, multivesicular bodies (MVBs) form and fuse with membrane to release exosomes.

Exosomes are vesicular structures containing genetic information. Recently, exosomes are being utilized as drug carriers. These systems are observed to be stable, specific, and safe. Moreover, delivery of exosomes shows less immunogenic affects. Further surface modifications and conjugation with liposomes enhances the therapeutic effects. Based on a previous study, intranasal delivery of exosomes loaded with a Stat3 inhibitor reduced brain inflammation and slowed brain tumor growth. [44]

Depiction of a dendrimer. A dendron represents a single unit of a dendrimer. Dendrimer and dendron.jpg
Depiction of a dendrimer. A dendron represents a single unit of a dendrimer.

Dendrimers

Dendrimers are polymeric macromolecules with a branched network similar to a tree structure. Generally, they are spherical and homogeneous. Surface charge and molecule chemistry can play crucial role with drug interaction and release. Poly(amidoamine) (PAMAM) dendrimers are the most commonly used system. A study investigated potential application of dendrimer-based formulation of haloperidol. Intranasal administration showed improved targeting, and solubility as well as high concentrations in the brain. [45] Drugs can be loaded in dendrimers through formulation and nanoconstruct. [46]

Importance of physiochemical properties

For drug delivery systems to bypass the blood brain barrier, modifications of physiochemical properties can enhance safety and efficacy. Size, surface charge, and lipophilicity play a major role in substance bypassing the blood brain barrier. Smaller, positively charged, or more lipophilic molecules enhance efficacy of nose-to-brain delivery. Decrease in delivery system size increases permeation. As the membrane is negatively charged, a particle with positive surface charge interacts electrostatically which enhances bioadhesion. Carriers with more lipophilicity exert better mucoadhesion and residence time. Drug system pH, solubility, and hydrogen bonding potential are other physiochemical properties which should be evaluated.

Related Research Articles

Nanomedicine is the medical application of nanotechnology. Nanomedicine ranges from the medical applications of nanomaterials and biological devices, to nanoelectronic biosensors, and even possible future applications of molecular nanotechnology such as biological machines. Current problems for nanomedicine involve understanding the issues related to toxicity and environmental impact of nanoscale materials.

<span class="mw-page-title-main">Liposome</span> Composite structures made of phospholipids and may contain small amounts of other molecules

A liposome is a small artificial vesicle, spherical in shape, having at least one lipid bilayer. Due to their hydrophobicity and/or hydrophilicity, biocompatibility, particle size and many other properties, liposomes can be used as drug delivery vehicles for administration of pharmaceutical drugs and nutrients, such as lipid nanoparticles in mRNA vaccines, and DNA vaccines. Liposomes can be prepared by disrupting biological membranes.

<span class="mw-page-title-main">Dendrimer</span> Highly ordered, branched polymeric molecule

Dendrimers are highly ordered, branched polymeric molecules. Synonymous terms for dendrimer include arborols and cascade molecules. Typically, dendrimers are symmetric about the core, and often adopt a spherical three-dimensional morphology. The word dendron is also encountered frequently. A dendron usually contains a single chemically addressable group called the focal point or core. The difference between dendrons and dendrimers is illustrated in the top figure, but the terms are typically encountered interchangeably.

<span class="mw-page-title-main">Drug delivery</span> Methods for delivering drugs to target sites

Drug delivery refers to approaches, formulations, manufacturing techniques, storage systems, and technologies involved in transporting a pharmaceutical compound to its target site to achieve a desired therapeutic effect. Principles related to drug preparation, route of administration, site-specific targeting, metabolism, and toxicity are used to optimize efficacy and safety, and to improve patient convenience and compliance. Drug delivery is aimed at altering a drug's pharmacokinetics and specificity by formulating it with different excipients, drug carriers, and medical devices. There is additional emphasis on increasing the bioavailability and duration of action of a drug to improve therapeutic outcomes. Some research has also been focused on improving safety for the person administering the medication. For example, several types of microneedle patches have been developed for administering vaccines and other medications to reduce the risk of needlestick injury.

Targeted drug delivery, sometimes called smart drug delivery, is a method of delivering medication to a patient in a manner that increases the concentration of the medication in some parts of the body relative to others. This means of delivery is largely founded on nanomedicine, which plans to employ nanoparticle-mediated drug delivery in order to combat the downfalls of conventional drug delivery. These nanoparticles would be loaded with drugs and targeted to specific parts of the body where there is solely diseased tissue, thereby avoiding interaction with healthy tissue. The goal of a targeted drug delivery system is to prolong, localize, target and have a protected drug interaction with the diseased tissue. The conventional drug delivery system is the absorption of the drug across a biological membrane, whereas the targeted release system releases the drug in a dosage form. The advantages to the targeted release system is the reduction in the frequency of the dosages taken by the patient, having a more uniform effect of the drug, reduction of drug side-effects, and reduced fluctuation in circulating drug levels. The disadvantage of the system is high cost, which makes productivity more difficult, and the reduced ability to adjust the dosages.

<span class="mw-page-title-main">Nasal administration</span> Administration of drugs through the nose

Nasal administration, popularly known as snorting, is a route of administration in which drugs are insufflated through the nose. It can be a form of either topical administration or systemic administration, as the drugs thus locally delivered can go on to have either purely local or systemic effects. Nasal sprays are locally acting drugs such as decongestants for cold and allergy treatment, whose systemic effects are usually minimal. Examples of systemically active drugs available as nasal sprays are migraine drugs, rescue medications for overdose and seizure emergencies, hormone treatments, nicotine nasal spray, and nasal vaccines such as live attenuated influenza vaccine.

<span class="mw-page-title-main">Lipid-based nanoparticle</span> Novel drug delivery system

Lipid-based nanoparticles are very small spherical particles composed of lipids. They are a novel pharmaceutical drug delivery system, and a novel pharmaceutical formulation. There are many subclasses of lipid-based nanoparticles such as: lipid nanoparticles (LNPs), solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs).

<span class="mw-page-title-main">Vectors in gene therapy</span>

Gene therapy utilizes the delivery of DNA into cells, which can be accomplished by several methods, summarized below. The two major classes of methods are those that use recombinant viruses and those that use naked DNA or DNA complexes.

<span class="mw-page-title-main">Sonodynamic therapy</span>

Sonodynamic therapy (SDT) is a noninvasive treatment, often used for tumor irradiation, that utilizes a sonosensitizer and the deep penetration of ultrasound to treat lesions of varying depths by reducing target cell number and preventing future tumor growth. Many existing cancer treatment strategies cause systemic toxicity or cannot penetrate tissue deep enough to reach the entire tumor; however, emerging ultrasound stimulated therapies could offer an alternative to these treatments with their increased efficiency, greater penetration depth, and reduced side effects. Sonodynamic therapy could be used to treat cancers and other diseases, such as atherosclerosis, and diminish the risk associated with other treatment strategies since it induces cytotoxic effects only when externally stimulated by ultrasound and only at the cancerous region, as opposed to the systemic administration of chemotherapy drugs.

Nanoparticles for drug delivery to the brain is a method for transporting drug molecules across the blood–brain barrier (BBB) using nanoparticles. These drugs cross the BBB and deliver pharmaceuticals to the brain for therapeutic treatment of neurological disorders. These disorders include Parkinson's disease, Alzheimer's disease, schizophrenia, depression, and brain tumors. Part of the difficulty in finding cures for these central nervous system (CNS) disorders is that there is yet no truly efficient delivery method for drugs to cross the BBB. Antibiotics, antineoplastic agents, and a variety of CNS-active drugs, especially neuropeptides, are a few examples of molecules that cannot pass the BBB alone. With the aid of nanoparticle delivery systems, however, studies have shown that some drugs can now cross the BBB, and even exhibit lower toxicity and decrease adverse effects throughout the body. Toxicity is an important concept for pharmacology because high toxicity levels in the body could be detrimental to the patient by affecting other organs and disrupting their function. Further, the BBB is not the only physiological barrier for drug delivery to the brain. Other biological factors influence how drugs are transported throughout the body and how they target specific locations for action. Some of these pathophysiological factors include blood flow alterations, edema and increased intracranial pressure, metabolic perturbations, and altered gene expression and protein synthesis. Though there exist many obstacles that make developing a robust delivery system difficult, nanoparticles provide a promising mechanism for drug transport to the CNS.

Nanoparticle drug delivery systems are engineered technologies that use nanoparticles for the targeted delivery and controlled release of therapeutic agents. The modern form of a drug delivery system should minimize side-effects and reduce both dosage and dosage frequency. Recently, nanoparticles have aroused attention due to their potential application for effective drug delivery.

Hamid Ghandehari is an Iranian-American drug delivery research scientist, and a professor in the Departments of Pharmaceutics and Pharmaceutical Chemistry and Biomedical Engineering at the University of Utah. His research is focused in recombinant polymers for drug and gene delivery, nanotoxicology of dendritic and inorganic constructs, water-soluble polymers for targeted delivery and poly(amidoamine) dendrimers for oral delivery.

Nanoneuroscience is an interdisciplinary field that integrates nanotechnology and neuroscience. One of its main goals is to gain a detailed understanding of how the nervous system operates and, thus, how neurons organize themselves in the brain. Consequently, creating drugs and devices that are able to cross the blood brain barrier (BBB) are essential to allow for detailed imaging and diagnoses. The blood brain barrier functions as a highly specialized semipermeable membrane surrounding the brain, preventing harmful molecules that may be dissolved in the circulation blood from entering the central nervous system.

<span class="mw-page-title-main">Dextran drug delivery systems</span> Polymeric drug carrier

Dextran drug delivery systems involve the use of the natural glucose polymer dextran in applications as a prodrug, nanoparticle, microsphere, micelle, and hydrogel drug carrier in the field of targeted and controlled drug delivery. According to several in vitro and animal research studies, dextran carriers reduce off-site toxicity and improve local drug concentration at the target tissue site. This technology has significant implications as a potential strategy for delivering therapeutics to treat cancer, cardiovascular diseases, pulmonary diseases, bone diseases, liver diseases, colonic diseases, infections, and HIV.

<span class="mw-page-title-main">Focused ultrasound for intracranial drug delivery</span> Medical technique

Focused ultrasound for intracrainial drug delivery is a non-invasive technique that uses high-frequency sound waves to disrupt tight junctions in the blood–brain barrier (BBB), allowing for increased passage of therapeutics into the brain. The BBB normally blocks nearly 98% of drugs from accessing the central nervous system, so FUS has the potential to address a major challenge in intracranial drug delivery by providing targeted and reversible BBB disruption. Using FUS to enhance drug delivery to the brain could significantly improve patient outcomes for a variety of diseases including Alzheimer's disease, Parkinson's disease, and brain cancer.

<span class="mw-page-title-main">Reduction-sensitive nanoparticles</span> Drug delivery method

Reduction-sensitive nanoparticles (RSNP) consist of nanocarriers that are chemically responsive to reduction. Drug delivery systems using RSNP can be loaded with different drugs that are designed to be released within a concentrated reducing environment, such as the tumor-targeted microenvironment. Reduction-Sensitive Nanoparticles provide an efficient method of targeted drug delivery for the improved controlled release of medication within localized areas of the body.

pH-responsive tumor-targeted drug delivery is a specialized form of targeted drug delivery that utilizes nanoparticles to deliver therapeutic drugs directly to cancerous tumor tissue while minimizing its interaction with healthy tissue. Scientists have used drug delivery as a way to modify the pharmacokinetics and targeted action of a drug by combining it with various excipients, drug carriers, and medical devices. These drug delivery systems have been created to react to the pH environment of diseased or cancerous tissues, triggering structural and chemical changes within the drug delivery system. This form of targeted drug delivery is to localize drug delivery, prolongs the drug's effect, and protect the drug from being broken down or eliminated by the body before it reaches the tumor.

Ultrasound-triggered drug delivery using stimuli-responsive hydrogels refers to the process of using ultrasound energy for inducing drug release from hydrogels that are sensitive to acoustic stimuli. This method of approach is one of many stimuli-responsive drug delivery-based systems that has gained traction in recent years due to its demonstration of localization and specificity of disease treatment. Although recent developments in this field highlight its potential in treating certain diseases such as COVID-19, there remain many major challenges that need to be addressed and overcome before more related biomedical applications are clinically translated into standard of care.

<span class="mw-page-title-main">Intravesical drug delivery</span> Intravesical drug delivery, drug delivery to the bladder

Intravesical drug delivery is the delivery of medications directly into the bladder by urinary catheter. This method of drug delivery is used to directly target diseases of the bladder such as interstitial cystitis and bladder cancer, but currently faces obstacles such as low drug retention time due to washing out with urine and issues with the low permeability of the bladder wall itself. Due to the advantages of directly targeting the bladder, as well as the effectiveness of permeability enhancers, advances in intravesical drug carriers, and mucoadhesive, intravesical drug delivery is becoming more effective and of increased interest in the medical community.

Immunoliposome therapy is a targeted drug delivery method that involves the use of liposomes coupled with monoclonal antibodies to deliver therapeutic agents to specific sites or tissues in the body. The antibody modified liposomes target tissue through cell-specific antibodies with the release of drugs contained within the assimilated liposomes. Immunoliposome aims to improve drug stability, personalize treatments, and increased drug efficacy. This form of therapy has been used to target specific cells, protecting the encapsulated drugs from degradation in order to enhance their stability, to facilitate sustained drug release and hence to advance current traditional cancer treatment.

References

  1. ↑ Erdő, Franciska; Bors, Luca Anna; Farkas, Dániel; Bajza, Ágnes; Gizurarson, Sveinbjörn (October 2018). "Evaluation of intranasal delivery route of drug administration for brain targeting". Brain Research Bulletin. 143: 155–170. doi:10.1016/j.brainresbull.2018.10.009. hdl: 20.500.11815/1402 . PMID   30449731. S2CID   53027303.
  2. ↑ Park, Haesun; Otte, Andrew; Park, Kinam (2022-02-01). "Evolution of drug delivery systems: From 1950 to 2020 and beyond". Journal of Controlled Release. 342: 53–65. doi:10.1016/j.jconrel.2021.12.030. ISSN   0168-3659. PMC   8840987 . PMID   34971694.
  3. ↑ Park, Kinam (2014-09-28). "Controlled drug delivery systems: Past forward and future back". Journal of Controlled Release. 30th Anniversary Special Issue. 190: 3–8. doi:10.1016/j.jconrel.2014.03.054. ISSN   0168-3659. PMC   4142099 . PMID   24794901.
  4. ↑ Crowe, Tyler P.; Greenlee, M. Heather West; Kanthasamy, Anumantha G.; Hsu, Walter H. (2018-02-15). "Mechanism of intranasal drug delivery directly to the brain". Life Sciences. 195: 44–52. doi:10.1016/j.lfs.2017.12.025. ISSN   0024-3205. PMID   29277310.
  5. ↑ Crowe, Tyler P.; Greenlee, M. Heather West; Kanthasamy, Anumantha G.; Hsu, Walter H. (2018-02-15). "Mechanism of intranasal drug delivery directly to the brain". Life Sciences. 195: 44–52. doi:10.1016/j.lfs.2017.12.025. ISSN   1879-0631. PMID   29277310.
  6. ↑ Crowe, Tyler P.; Hsu, Walter H. (March 2022). "Evaluation of Recent Intranasal Drug Delivery Systems to the Central Nervous System". Pharmaceutics. 14 (3): 629. doi: 10.3390/pharmaceutics14030629 . ISSN   1999-4923. PMC   8950509 . PMID   35336004.
  7. ↑ Veronesi, Michael C.; Alhamami, Mosa; Miedema, Shelby B.; Yun, Yeonhee; Ruiz-Cardozo, Miguel; Vannier, Michael W. (2020). "Imaging of intranasal drug delivery to the brain". American Journal of Nuclear Medicine and Molecular Imaging. 10 (1): 1–31. ISSN   2160-8407. PMC   7076302 . PMID   32211216.
  8. ↑ Emre, Ceren; Arroyo-García, Luis E.; Do, Khanh V.; Jun, Bokkyoo; Ohshima, Makiko; Alcalde, Silvia Gómez; Cothern, Megan L.; Maioli, Silvia; Nilsson, Per; Hjorth, Erik; Fisahn, André; Bazan, Nicolas G.; Schultzberg, Marianne (2022-03-21). "Intranasal delivery of pro-resolving lipid mediators rescues memory and gamma oscillation impairment in AppNL-G-F/NL-G-F mice". Communications Biology. 5 (1): 245. doi:10.1038/s42003-022-03169-3. ISSN   2399-3642. PMC   8938447 . PMID   35314851.
  9. ↑ Cheng, Yu-Sung; Chen, Zih-ten; Liao, Tai-Yan; Lin, Chen; Shen, Howard C-H; Wang, Ya-Han; Chang, Chi-Wei; Liu, Ren-Shyan; Chen, Rita P-Y; Tu, Pang-hsien (May 2017). "An intranasally delivered peptide drug ameliorates cognitive decline in Alzheimer transgenic mice". EMBO Molecular Medicine. 9 (5): 703–715. doi:10.15252/emmm.201606666. ISSN   1757-4676. PMC   5412883 . PMID   28356312.
  10. ↑ Al Harthi, Sitah; Alavi, Seyed Ebrahim; Radwan, Mahasen Ali; El Khatib, Mona Mohamed; AlSarra, Ibrahim Abdullah (2019-07-02). "Nasal delivery of donepezil HCl-loaded hydrogels for the treatment of Alzheimer's disease". Scientific Reports. 9 (1): 9563. Bibcode:2019NatSR...9.9563A. doi:10.1038/s41598-019-46032-y. ISSN   2045-2322. PMC   6606601 . PMID   31266990.
  11. ↑ Su, Yu; Sun, Bixi; Gao, Xiaoshu; Dong, Xinyue; Fu, Lanbo; Zhang, Yingxin; Li, Zhulin; Wang, Yue; Jiang, Hongyu; Han, Bing (2020). "Intranasal Delivery of Targeted Nanoparticles Loaded With miR-132 to Brain for the Treatment of Neurodegenerative Diseases". Frontiers in Pharmacology. 11: 1165. doi: 10.3389/fphar.2020.01165 . ISSN   1663-9812. PMC   7424054 . PMID   32848773.
  12. ↑ Fonseca, Leonor C.; Lopes, João A.; Vieira, João; Viegas, Cláudia; Oliveira, Cláudia S.; Hartmann, Rafael P.; Fonte, Pedro (2021-04-01). "Intranasal drug delivery for treatment of Alzheimer's disease". Drug Delivery and Translational Research. 11 (2): 411–425. doi:10.1007/s13346-021-00940-7. ISSN   2190-3948. PMID   33638130. S2CID   232066300.
  13. ↑ Ullah, Irfan; Chung, Kunho; Bae, Sumin; Li, Yan; Kim, Chunggu; Choi, Boyoung; Nam, Hye Yeong; Kim, Sun Hwa; Yun, Chae-Ok; Lee, Kuen Yong; Kumar, Priti; Lee, Sang-Kyung (2020-04-06). "Nose-to-Brain Delivery of Cancer-Targeting Paclitaxel-Loaded Nanoparticles Potentiates Antitumor Effects in Malignant Glioblastoma". Molecular Pharmaceutics. 17 (4): 1193–1204. doi:10.1021/acs.molpharmaceut.9b01215. ISSN   1543-8384. PMID   31944768. S2CID   210698321.
  14. ↑ Chung, Kunho; Ullah, Irfan; Kim, Nahyeon; Lim, Jaeyeoung; Shin, Jungah; Lee, Sangah C.; Jeon, Sangmin; Kim, Sun Hwa; Kumar, Priti; Lee, Sang-Kyung (2020-07-02). "Intranasal delivery of cancer-targeting doxorubicin-loaded PLGA nanoparticles arrests glioblastoma growth". Journal of Drug Targeting. 28 (6): 617–626. doi:10.1080/1061186X.2019.1706095. ISSN   1061-186X. PMID   31852284. S2CID   209417799.
  15. ↑ Ha, Junkyu; Kim, Minkyung; Lee, Youngki; Lee, Minhyung (2021-09-17). "Intranasal delivery of self-assembled nanoparticles of therapeutic peptides and antagomirs elicits anti-tumor effects in an intracranial glioblastoma model". Nanoscale. 13 (35): 14745–14759. doi:10.1039/D1NR03455C. ISSN   2040-3372. PMID   34474460.
  16. ↑ Liu, Shanshan; Yang, Shili; Ho, Paul C. (January 2018). "Intranasal administration of carbamazepine-loaded carboxymethyl chitosan nanoparticles for drug delivery to the brain". Asian Journal of Pharmaceutical Sciences. 13 (1): 72–81. doi:10.1016/j.ajps.2017.09.001. PMC   7032105 . PMID   32104380.
  17. ↑ Wang, Julie Tzu-Wen; Rodrigo, Ana C.; Patterson, Anna K.; Hawkins, Kirsten; Aly, Mazen M. S.; Sun, Jia; Al Jamal, Khuloud T.; Smith, David K. (July 2021). "Enhanced Delivery of Neuroactive Drugs via Nasal Delivery with a Self-Healing Supramolecular Gel". Advanced Science. 8 (14): 2101058. doi:10.1002/advs.202101058. ISSN   2198-3844. PMC   8292877 . PMID   34029010.
  18. ↑ Tanaka, Akiko; Furubayashi, Tomoyuki; Arai, Mari; Inoue, Daisuke; Kimura, Shunsuke; Kiriyama, Akiko; Kusamori, Kosuke; Katsumi, Hidemasa; Yutani, Reiko; Sakane, Toshiyasu; Yamamoto, Akira (2018-03-05). "Delivery of Oxytocin to the Brain for the Treatment of Autism Spectrum Disorder by Nasal Application". Molecular Pharmaceutics. 15 (3): 1105–1111. doi:10.1021/acs.molpharmaceut.7b00991. ISSN   1543-8384. PMID   29338251.
  19. ↑ Chang, Jui-Chih; Chao, Yi-Chun; Chang, Huei-Shin; Wu, Yu-Ling; Chang, Hui-Ju; Lin, Yong-Shiou; Cheng, Wen-Ling; Lin, Ta-Tsung; Liu, Chin-San (2021-05-19). "Intranasal delivery of mitochondria for treatment of Parkinson's Disease model rats lesioned with 6-hydroxydopamine". Scientific Reports. 11 (1): 10597. Bibcode:2021NatSR..1110597C. doi:10.1038/s41598-021-90094-w. ISSN   2045-2322. PMC   8136477 . PMID   34011937.
  20. ↑ Wang, Julie Tzu-Wen; Rodrigo, Ana C.; Patterson, Anna K.; Hawkins, Kirsten; Aly, Mazen M. S.; Sun, Jia; Al Jamal, Khuloud T.; Smith, David K. (July 2021). "Enhanced Delivery of Neuroactive Drugs via Nasal Delivery with a Self-Healing Supramolecular Gel". Advanced Science. 8 (14): 2101058. doi:10.1002/advs.202101058. ISSN   2198-3844. PMC   8292877 . PMID   34029010.
  21. ↑ Peng, Huan; Li, Yan; Ji, Weihong; Zhao, Ruichen; Lu, Zhiguo; Shen, Jie; Wu, Yanyue; Wang, Jianze; Hao, Qiulian; Wang, Jingwen; Wang, Wenli; Yang, Jun; Zhang, Xin (2022-01-25). "Intranasal Administration of Self-Oriented Nanocarriers Based on Therapeutic Exosomes for Synergistic Treatment of Parkinson's Disease". ACS Nano. 16 (1): 869–884. doi:10.1021/acsnano.1c08473. ISSN   1936-0851. PMID   34985280. S2CID   245703239.
  22. ↑ Bi, Chenchen; Wang, Aiping; Chu, Yongchao; Liu, Sha; Mu, Hongjie; Liu, Wanhui; Wu, Zimei; Sun, Kaoxiang; Li, Youxin (2016-12-07). "Intranasal delivery of rotigotine to the brain with lactoferrin-modified PEG-PLGA nanoparticles for Parkinson's disease treatment". International Journal of Nanomedicine. 11: 6547–6559. doi: 10.2147/IJN.S120939 . PMC   5153272 . PMID   27994458.
  23. ↑ Marwari, Subhi; Poulsen, Anders; Shih, Norrapat; Lakshminarayanan, Rajamani; Kini, R. Manjunatha; Johannes, Charles William; Dymock, Brian William; Dawe, Gavin Stewart (October 2019). "Intranasal administration of a stapled relaxin-3 mimetic has anxiolytic- and antidepressant-like activity in rats". British Journal of Pharmacology. 176 (20): 3899–3923. doi:10.1111/bph.14774. ISSN   0007-1188. PMC   6811745 . PMID   31220339.
  24. ↑ Wang, Qiang-Song; Li, Kefeng; Gao, Li-Na; Zhang, Ye; Lin, Ke-Ming; Cui, Yuan-Lu (2020-05-19). "Intranasal delivery of berberine via in situ thermoresponsive hydrogels with non-invasive therapy exhibits better antidepressant-like effects". Biomaterials Science. 8 (10): 2853–2865. doi:10.1039/C9BM02006C. ISSN   2047-4849. PMID   32270794. S2CID   215607435.
  25. ↑ Mahmoud, Khaled Y.; Elhesaisy, Nahla A.; Rashed, Abdelrahman R.; Mikhael, Ebram S.; Fadl, Mahmoud I.; Elsadek, Mahmoud S.; Mohamed, Merna A.; Mostafa, Merna A.; Hassan, Mohamed A.; Halema, Omar M.; Elnemer, Youssef H.; Swidan, Shady A. (2023-01-10). "Exploring the potential of intranasally administered naturally occurring quercetin loaded into polymeric nanocapsules as a novel platform for the treatment of anxiety". Scientific Reports. 13 (1): 510. Bibcode:2023NatSR..13..510M. doi:10.1038/s41598-023-27665-6. ISSN   2045-2322. PMC   9831377 . PMID   36627363.
  26. ↑ Serova, L. I.; Laukova, M.; Alaluf, L. G.; Pucillo, L.; Sabban, E. L. (2014-01-01). "Intranasal neuropeptide Y reverses anxiety and depressive-like behavior impaired by single prolonged stress PTSD model". European Neuropsychopharmacology. 24 (1): 142–147. doi:10.1016/j.euroneuro.2013.11.007. ISSN   0924-977X. PMID   24326087. S2CID   9446589.
  27. ↑ Russell, Janice; Maguire, Sarah; Hunt, Glenn E.; Kesby, Alice; Suraev, Anastasia; Stuart, Jordyn; Booth, Jessica; McGregor, Iain S. (2018-01-01). "Intranasal oxytocin in the treatment of anorexia nervosa: Randomized controlled trial during re-feeding". Psychoneuroendocrinology. 87: 83–92. doi:10.1016/j.psyneuen.2017.10.014. ISSN   0306-4530. PMID   29049935. S2CID   23957504.
  28. ↑ Kashyap, Bhavani; Hanson, Leah R.; Frey II, William H. (2020-01-01). "Intranasal Insulin: a Treatment Strategy for Addiction". Neurotherapeutics. 17 (1): 105–115. doi:10.1007/s13311-019-00822-4. ISSN   1878-7479. PMC   7007475 . PMID   31898283.
  29. ↑ Kasina, Vishal; Mownn, Robert J.; Bahal, Raman; Sartor, Gregory C. (July 2022). "Nanoparticle delivery systems for substance use disorder". Neuropsychopharmacology. 47 (8): 1431–1439. doi:10.1038/s41386-022-01311-7. ISSN   1740-634X. PMC   8960682 . PMID   35351961.
  30. ↑ Pang, Lulu; Zhu, Siqing; Ma, Jinqiu; Zhu, Lin; Liu, Yijing; Ou, Ge; Li, Ruiteng; Wang, Yaxin; Liang, Yi; Jin, Xu; Du, Lina; Jin, Yiguang (2021-07-01). "Intranasal temperature-sensitive hydrogels of cannabidiol inclusion complex for the treatment of post-traumatic stress disorder". Acta Pharmaceutica Sinica B. 11 (7): 2031–2047. doi:10.1016/j.apsb.2021.01.014. ISSN   2211-3835. PMC   8343172 . PMID   34386336.
  31. ↑ Ou, Ge; Li, Qian; Zhu, Lin; Zhang, Yuanyuan; Liu, Yijing; Li, Xin; Du, Lina; Jin, Yiguang (2022-03-01). "Intranasal hydrogel of armodafinil hydroxypropyl-β-cyclodextrin inclusion complex for the treatment of post-traumatic stress disorder". Saudi Pharmaceutical Journal. 30 (3): 265–282. doi:10.1016/j.jsps.2022.01.009. ISSN   1319-0164. PMC   9051980 . PMID   35498223.
  32. ↑ Gozes, Illana (2011-02-01). "Microtubules, schizophrenia and cognitive behavior: Preclinical development of davunetide (NAP) as a peptide-drug candidate". Peptides. 32 (2): 428–431. doi:10.1016/j.peptides.2010.10.030. ISSN   0196-9781. PMID   21050875. S2CID   31105309.
  33. ↑ Assadpour, Sara; Shiran, Mohammad Reza; Asadi, Peyman; Akhtari, Javad; Sahebkar, Amirhossein (2022-01-15). "Harnessing Intranasal Delivery Systems of Sumatriptan for the Treatment of Migraine". BioMed Research International. 2022: e3692065. doi: 10.1155/2022/3692065 . ISSN   2314-6133. PMC   8783720 . PMID   35075426.
  34. ↑ "Trudhesa: Is This Novel Approach to Migraine Medication Right for You?". MigraineAgain.com. Retrieved 2024-08-24.
  35. ↑ Cooper, Wade; Ray, Sutapa; Aurora, Sheena K.; Shrewsbury, Stephen B.; Fuller, Christopher; Davies, Greg; Hoekman, John (2022-12-01). "Delivery of Dihydroergotamine Mesylate to the Upper Nasal Space for the Acute Treatment of Migraine: Technology in Action". Journal of Aerosol Medicine and Pulmonary Drug Delivery. 35 (6): 321–332. doi:10.1089/jamp.2022.0005. ISSN   1941-2711. PMC   9807280 . PMID   36108289.
  36. ↑ Lee, David; Minko, Tamara (December 2021). "Nanotherapeutics for Nose-to-Brain Drug Delivery: An Approach to Bypass the Blood Brain Barrier". Pharmaceutics. 13 (12): 2049. doi: 10.3390/pharmaceutics13122049 . ISSN   1999-4923. PMC   8704573 . PMID   34959331.
  37. ↑ Lee, David; Minko, Tamara (December 2021). "Nanotherapeutics for Nose-to-Brain Drug Delivery: An Approach to Bypass the Blood Brain Barrier". Pharmaceutics. 13 (12): 2049. doi: 10.3390/pharmaceutics13122049 . ISSN   1999-4923. PMC   8704573 . PMID   34959331.
  38. ↑ Dhaliwal, Harkiranpreet Kaur; Fan, Yingfang; Kim, Jonghan; Amiji, Mansoor M. (2020-06-01). "Intranasal Delivery and Transfection of mRNA Therapeutics in the Brain Using Cationic Liposomes". Molecular Pharmaceutics. 17 (6): 1996–2005. doi:10.1021/acs.molpharmaceut.0c00170. ISSN   1543-8384. PMID   32365295. S2CID   218506234.
  39. ↑ Arora, Deepshi; Bhatt, Shailendra; Kumar, Manish; Verma, Ravinder; Taneja, Yugam; Kaushal, Nikita; Tiwari, Abhishek; Tiwari, Varsha; Alexiou, Athanasios; Albogami, Sarah; Alotaibi, Saqer S.; Mittal, Vineet; Singla, Rajeev K.; Kaushik, Deepak; Batiha, Gaber El-Saber (2022). "QbD-based rivastigmine tartrate-loaded solid lipid nanoparticles for enhanced intranasal delivery to the brain for Alzheimer's therapeutics". Frontiers in Aging Neuroscience. 14: 960246. doi: 10.3389/fnagi.2022.960246 . ISSN   1663-4365. PMC   9407039 . PMID   36034142. (Retracted, see doi:10.3389/fnagi.2024.1399271, PMID   38605858 . If this is an intentional citation to a retracted paper, please replace {{ retracted |...}} with {{ retracted |...|intentional=yes}}.)
  40. ↑ Madane, Rohini G.; Mahajan, Hitendra S. (2016-05-03). "Curcumin-loaded nanostructured lipid carriers (NLCs) for nasal administration: design, characterization, and in vivo study". Drug Delivery. 23 (4): 1326–1334. doi: 10.3109/10717544.2014.975382 . ISSN   1071-7544. PMID   25367836. S2CID   28117605.
  41. ↑ Bayanati, Masoumeh; Khosroshahi, Abolfazl Ghafouri; Alvandi, Maryam; Mahboobian, Mohammad Mehdi (2021-03-13). "Fabrication of a Thermosensitive In Situ Gel Nanoemulsion for Nose to Brain Delivery of Temozolomide". Journal of Nanomaterials. 2021: e1546798. doi: 10.1155/2021/1546798 . ISSN   1687-4110.
  42. ↑ Yousfan, Amal; Rubio, Noelia; Natouf, Abdul Hakim; Daher, Aamal; Al-Kafry, Nedal; Venner, Kerrie; Kafa, Houmam (2020-08-03). "Preparation and characterisation of PHT-loaded chitosan lecithin nanoparticles for intranasal drug delivery to the brain". RSC Advances. 10 (48): 28992–29009. Bibcode:2020RSCAd..1028992Y. doi:10.1039/D0RA04890A. ISSN   2046-2069. PMC   9055806 . PMID   35520085.
  43. ↑ Shah, Pranav; Dubey, Priya; Vyas, Bhavin; Kaul, Ankur; Mishra, Anil Kumar; Chopra, Dimple; Patel, Priya (2021-01-01). "Lamotrigine loaded PLGA nanoparticles intended for direct nose to brain delivery in epilepsy: pharmacokinetic, pharmacodynamic and scintigraphy study". Artificial Cells, Nanomedicine, and Biotechnology. 49 (1): 511–522. doi: 10.1080/21691401.2021.1939709 . ISSN   2169-1401. PMID   34151674. S2CID   235493756.
  44. ↑ Zhuang, Xiaoying; Xiang, Xiaoyu; Grizzle, William; Sun, Dongmei; Zhang, Shuangqin; Axtell, Robert C.; Ju, Songwen; Mu, Jiangyao; Zhang, Lifeng; Steinman, Lawrence; Miller, Donald; Zhang, Huang-Ge (2011-10-01). "Treatment of Brain Inflammatory Diseases by Delivering Exosome Encapsulated Anti-inflammatory Drugs From the Nasal Region to the Brain". Molecular Therapy. 19 (10): 1769–1779. doi:10.1038/mt.2011.164. ISSN   1525-0016. PMC   3188748 . PMID   21915101.
  45. ↑ Katare, Yogesh K.; Daya, Ritesh P.; Sookram Gray, Christal; Luckham, Roger E.; Bhandari, Jayant; Chauhan, Abhay S.; Mishra, Ram K. (2015-09-08). "Brain Targeting of a Water Insoluble Antipsychotic Drug Haloperidol via the Intranasal Route Using PAMAM Dendrimer". Molecular Pharmaceutics. 12 (9): 3380–3388. doi: 10.1021/acs.molpharmaceut.5b00402 . ISSN   1543-8384. PMID   26226403.
  46. ↑ Chauhan, Abhay Singh (April 2018). "Dendrimers for Drug Delivery". Molecules. 23 (4): 938. doi: 10.3390/molecules23040938 . ISSN   1420-3049. PMC   6017392 . PMID   29670005.
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